Abstract Retinopathy of prematurity (ROP) and diabetic retinopathy (DR) are the two leading causes of blindness in children and working-age adults, respectively. Both of these devastating conditions are characterized by pathological retinal angiogenesis that is preceded by a hypoxic stimulus. Fatty Acid Binding Protein 4 (FABP4) is an intracellular lipid chaperone that reversibly binds hydrophobic ligands. FABP4 plays a critical role in maintenance of glucose and lipid homeostasis. The biologic relevance of FABP4 is underscored by the findings that FABP4 knock-out (FABP4-/-) mice exhibit marked protection against insulin resistance, atherosclerosis and fatty liver disease. Although FABP4 was initially thought to be primarily expressed in adipocytes and macrophages, we recently made a novel observation that FABP4 is also expressed in certain endothelial cells (ECs) in normal tissues. The role of FABP4 in ECs is not known, but our recent studies strongly suggest a pro-angiogenic role. To begin to investigate the potential role of FABP4 in pathological retinal angiogenesis, we first characterized the expression pattern of FABP4 mRNA in a mouse model of oxygen-induced-retinopathy (OIR) and found that FABP4 mRNA levels are significantly increased in the OIR group compared to the control group at postnatal day (P) 15. To examine this hypothesis further, we exposed FABP4-/- mice to the OIR model and found that FABP4-/- mice are significantly protected against pathological retinal angiogenesis. Furthermore, FABP4 expression was localized to ECs in neovascular tufts, but not to those in adjacent non-pathological vessels on flat-mount preparations of P17-OIR samples. Based on these novel data, we hypothesize that FABP4 plays a critical role in enhancing the pathological retinal neovascularization in OIR by promoting EC activation and angiogenesis. The specific aims (SA) of this proposal are to: (1) determine the mechanisms by which FABP4 deficiency protects against pathological neo-vascularization in the OIR model; and (2) assess the ability of a small-molecule inhibitor of FABP4 to prevent and treat pathological angiogenesis in the mouse model of OIR. These studies have the potential to identify FABP4 as a novel therapeutic target in proliferative retinopathies.